Liquid pharmaceutical composition

ABSTRACT

The present invention provides a physically and chemically stable pharmaceutical liquid composition including sodium picosulfate, magnesium oxide, citric acid and malic acid and methods of making and using such a composition.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.15/822,298, filed Nov. 27, 2017 (now U.S. Pat. No. 10,624,879), which isa continuation of U.S. application Ser. No. 15/214,768, filed Jul. 20,2016 (now U.S. Pat. No. 9,827,231), which is a continuation ofInternational Appl. No. PCT/KR2014/005512, filed Jun. 23, 2014, whichclaims the benefit of Republic of Korea Patent Application Number10-2014-0032242, filed Mar. 19, 2014. The related applications, and PCTInternational Publication Number WO2015/141897 (the publication ofPCT/KR2014/005512), are each hereby incorporated by reference in theirentirety.

TECHNICAL FIELD

The present invention relates to a pharmaceutical liquid composition,and more particularly to a physically and chemically stablepharmaceutical liquid composition including sodium picosulfate,magnesium oxide, citric acid and malic acid.

BACKGROUND

A medicine including citric acid magnesium oxide and sodium picosulfateis used as a purgative for pretreatment at the time of surgery,colonoscopy or colon X-ray inspection, and is currently commerciallyavailable as the name of Picolight power. This medicine is white powderwhich is used by being dissolved in water when taken orally.

The medicine in the dosage form of powder should be taken by dissolvingone package in a suitable amount of water. However, some patients mayfeel inconvenient when dissolving the medicine in water, and somepatients who fail to recognize how to use properly may drink water afterputting the powder into the mouth. In this case, exothermic reactionoccurring when the powder is dissolved in water may burn the patient'smouth.

Thus, the medicine in the form of powder may be dissolved in water inadvance and stored in a refrigerator or another storage space beforebeing taken. However, in this case, citric acid and magnesium oxide thatare chief ingredients may react with each other to become magnesiumcitrate, and the remaining magnesium oxide after reaction may acceleratethe precipitation of the magnesium citrate over time to sink to thebottom. Therefore, if the medicine is not diluted well with water whentaken, a proper effect cannot be achieved because the precipitatedamount cannot be taken. As the pH of the medicine is kept low, theamount of precipitation tends to be reduced. However, in this case,there arises a problem such that sodium picosulfate becomes unstable.

Therefore, in order to solve the problems described above, there is ademand for a physically and chemically stable pharmaceutical liquidcomposition.

SUMMARY

In view of the above, the present invention provides a physically andchemically stable pharmaceutical liquid composition including sodiumpicosulfate, magnesium oxide and citric acid.

However, objects of the present invention are not restricted to the oneset forth herein. The above and other objects of the present inventionwill become more apparent to one of ordinary skill in the art to whichthe present invention pertains by referencing the detailed descriptionof the present invention given below.

DETAILED DESCRIPTION

In accordance with an aspect of the present invention, there is provideda pharmaceutical liquid composition including sodium picosulfate,magnesium oxide, citric acid and malic acid.

The pharmaceutical liquid composition may be used for colon cleaning asa purgative for pretreatment at the time of surgery, colonoscopy orcolon X-ray inspection.

A one-time dose of the liquid composition may be different according tothe content of an effective ingredient, but may range from 50 mL to 500mL as a non-limiting example. In an exemplary embodiment, it may rangefrom 100 mL to 300 mL or may range from 150 mL to 200 mL, but it is notlimited thereto.

In order to remove the inconvenience when the medicine in the form ofpowder is taken by dissolving powder in water, it is intended to changethe dosage form from powder to liquid. However, the present inventionprovides a pharmaceutical liquid composition which is physically andchemically stable when stored.

As one example, in the pharmaceutical liquid composition, for 24 months,a content change of each ingredient may be within ±5.0 wt. % (weightpercent) with respect to the weight of each ingredient, and impurities.Substance A related to sodium picosulfate(4-[(pyridine-2-yl)(4-hydroxyphenyl)methyl]phenyl sodium sulfate) may begenerated at 2.0 wt. % or less. Further, the precipitate may not occur,or may occur at 5.0 vol. % (volume percent) or less.

According to experiments by the inventors of the present invention, inthe case of using organic acid or inorganic acid other than malic acid,it is difficult to expect the stability as described above. The malicacid may include both 1-malic acid and d-malic acid.

In order to have the stability described above, in one preferredexample, the pH of the pharmaceutical liquid preparation may range from4.1 to 5.4.

According to experiments by the inventors of the present invention, ithas been confirmed that superior stability is exhibited in the pH range.If the pH of the pharmaceutical liquid composition is less than 4.1,Substance A related to sodium picosulfate increases, and it is notpreferable because the patient may feel uncomfortable with strongsourness when taking the medicine. On the other hand, if the pH of thepharmaceutical liquid composition is greater than 5.4, it is notpreferable because it is difficult to dissolve magnesium oxide whichcauses the precipitation.

The pharmaceutical liquid composition of the present invention mayinclude a variety of excipients and purified water. The purified wateris used in order to prepare the medicine in the form of liquid, and theexcipients may be used for the excellent taste to increase themedication compliance and the stability of the pharmaceutical liquidcomposition.

For example, the excipients may include, but not limited to, a pHadjuster, a stabilizer, a preservative, a sweetener and a fragranceingredient.

The pH adjuster may be an alkalizing agent. In the case of thealkalizing agent, it is possible to adjust a reduction in pH due to themalic acid.

As the alkalizing agent, for example, sodium hydroxide, potassiumhydroxide, sodium bicarbonate, ammonia solution, potassium citrate,triethanolamine and sodium citrate and the like may be used, but it isnot limited thereto. In an exemplary embodiment, sodium hydroxide,potassium hydroxide, sodium citrate, and the like may be used, but it isnot limited thereto.

The sodium picosulfate, magnesium oxide, citric acid and malic acid mayhave a weight ratio of 0.003 to 0.009:1 to 3:3.5 to 10.5:0.01 to 13(sodium picosulfate:magnesium oxide:citric acid:malic acid).

An exemplary method of preparing a pharmaceutical liquid composition ofthe present invention will be described below.

The method may include the steps of weighing citric acid and magnesiumoxide to prepare a mixture, mixing malic acid and a pH adjuster with theprepared mixture, mixing sodium picosulfate with the mixture, and addingpurified water to the mixture.

The weighing may also include the step of weighing and separatelypreparing each of ingredients to be used.

In one example, before adding the purified water, a sweetener, afragrance ingredient, or a mixture thereof may be added to the mixtureor sterilized mixture. The sweetener and/or fragrance ingredient may beused for the excellent taste to increase the medication compliance.

Advantageous Effects

Embodiments of the present invention provide at least the followingeffects.

By providing a pharmaceutical liquid composition including sodiumpicosulfate, magnesium oxide, citric acid and malic acid, it is possibleto increase the medication compliance and convenience and the ease ofstorage and transport.

The effects of the present invention are not limited to theabove-described effects and other effects which are not described hereinwill become apparent to those skilled in the art from the followingdescription.

DESCRIPTION OF DRAWINGS

FIG. 1 is a process flow diagram illustrating a method of manufacturinga pharmaceutical liquid composition according to an embodiment of thepresent invention.

OTHER EMBODIMENTS

Although the present invention may be variously changed and includeseveral embodiments, particular embodiments shown in the drawings willbe described in detail in a detailed description. However, it is to beunderstood that the present invention is not limited to the particularembodiments, and various changes, equivalences and substitutions may bemade without departing from the scope and spirit of the invention.

EXAMPLES Example 1

A pharmaceutical liquid composition was prepared by dissolving, inpurified water in a weight ratio of 75, sodium picosulfate:magnesiumoxide:citric acid:dl-malic acid in a weight ratio of 0.005:1.75:6:4.19,sodium benzoate in a weight ratio of 0.043 as a preservative, disodiumedetate hydrate in a weight ratio of 0.035 as a stabilizer, sodiumhydroxide in a weight ratio of 2.1 as a pH adjuster, acesulfamepotassium in a weight ratio of 0.1, and sucralose in a weight ratio of0.1 as a sweetener, and a fragrance ingredient in orange flavor in aweight ratio of 0.043.

Comparative Example 1

A powder composition was prepared by including sodiumpicosulfate:magnesium oxide:citric acid in a weight ratio of0.005:1.75:6, sodium hydrogen carbonate in a weight ratio of 0.21 as anexcipient, acesulfame potassium qs (quantum satis) as a sweetener, and afragrance ingredient having orange flavor qs (quantum satis).

Example 2

The contents of sodium picosulfate, magnesium oxide and citric acid thatare main components of a solution obtained by dissolving the liquidcomposition of Example 1 in water of 150 mL were compared with those ofa solution obtained by dissolving the powder composition of ComparativeExample 1 in water of 150 mL. The content comparison method is anexperiment method pursuant to British Pharmacopoeia 2004 Compound SodiumPicosulfate Powder for Oral Solution and the measurement was made byhigh performance liquid chromatography. The results are shown in Table 1below.

TABLE 1 Ingredient Content Comparative Name Criteria Example 1 Example 1Sodium picosulfate 90.0~110.0% 100.7% 100.1% Magnesium oxide 90.0~110.0%101.0% 101.4% Citric acid 90.0~110.0% 100.1% 99.7%

As a result of the experiment, it can be seen from Table 1 that there isno substantial difference between the contents of the main components ofExample 1 and Comparative Example 1. Therefore, both the powdercomposition and the liquid composition are considered to have the sameeffect as a colon cleanser.

Example 3

A liquid composition was prepared by dissolving, in purified water in aweight ratio of 75, sodium picosulfate:magnesium oxide:citric acid in aweight ratio of 0.005:1.75:6, and adding, as a solubilizing agent, eachof polyoxyethylene hydrogenated castor oil, polyethylene sorbitanmonooleate, polyoxyethylene octyl dodecyl ether, polysorbate 20,polysorbate 60 and polysorbate 80 at 5.0 wt. % with respect to the totalliquid weight. The liquid composition was left under the roomtemperature conditions (25° C., 60%) to check whether precipitationoccurs, and a time point (day) when precipitation occurs at 5.0 vol. %on the bottom of a sample container was measured. The results are shownin Table 2 below.

TABLE 2 Room Temperature Conditions (when Raw Material Nameprecipitation occurs: day) Polyoxyethylene hydrogenated castor oil 20Polyethylene sorbitan monooleate 17 Polyoxyethylene octyl dodecyl ether17 Polysorbate 20 23 Polysorbate 60 22 Polysorbate 80 20

As can be seen in Table 2, it can be confirmed that precipitates areformed at 5.0 vol. % or more as a result of applying a solubilizingagent, and the solubilizing agent does not contribute to prevention ofprecipitation.

Example 4

A liquid composition was prepared by dissolving, in purified water in aweight ratio of 75, sodium picosulfate:magnesium oxide:citric acid in aweight ratio of 0.005:1.75:6, using, as organic acid in a weight ratioof 4.19, each of citric acid, dl-malic acid, maleic acid, tartrate,fumaric acid, lactic acid, sodium citrate, aspartic acid, succinic acid,glutamic acid, hydrochloric acid, phosphoric acid, sulfuric acid andacetic acid, and adding, as a pH adjuster, sodium hydroxide in a weightratio of 2.1 for each pH. The liquid composition was left for 24 monthsunder the room temperature conditions (25° C., 60%) to check whetherprecipitation occurs. A time point (day) when precipitation occurs at5.0 vol. % on the bottom of a sample container was measured and shown inTable 3 below. The content of the substance related to sodiumpicosulfate produced after 24 months was measured and shown in Table 4below.

TABLE 3 Room Temperature Conditions (when Raw Material Name pHprecipitation occurs: day) Sodium hydroxide + 5.4 2 Citric acid 4.7 184.1 280 Sodium hydroxide + 5.4 — dl-malic acid 4.7 — 4.1 — Sodiumhydroxide + 5.4 2 Maleic acid 4.7 10 4.1 350 Sodium hydroxide + 5.4 2Tartrate 4.7 2 4.1 77 Sodium hydroxide + 5.4 2 Fumaric acid 4.7 18 4.198 Sodium hydroxide + 5.4 2 Lactic acid 4.7 14 4.1 105 Sodiumhydroxide + 5.4 2 Sodium citrate 4.7 10 4.1 91 Sodium hydroxide + 5.4 2Aspartic acid 4.7 18 4.1 77 Sodium hydroxide + 5.4 2 Succinic acid 4.718 4.1 98 Sodium hydroxide + 5.4 2 Glutamic acid 4.7 14 4.1 98

As can be seen in Table 3, it can be confirmed that precipitation occurswithin 24 months in all cases of organic acids other than malic acid.

TABLE 4 Room Temperature Raw Material Name pH Conditions (wt. %) Sodiumhydroxide + 5.4 0.19 Citric acid 4.7 0.32 4.1 2.61 Sodium hydroxide +5.4 0.25 dl-malic acid 4.7 0.39 4.1 1.98 Sodium hydroxide + 5.4 0.31Maleic acid 4.7 0.49 4.1 2.91 Sodium hydroxide + 5.4 0.26 Tartrate 4.70.46 4.1 2.97 Sodium hydroxide + 5.4 0.18 Fumaric acid 4.7 0.60 4.1 2.75Sodium hydroxide + 5.4 0.26 Lactic acid 4.7 0.74 4.1 2.74 Sodiumhydroxide + 5.4 0.18 Sodium citrate 4.7 0.46 4.1 2.25 Sodium hydroxide +5.4 0.21 Aspartic acid 4.7 0.58 4.1 2.95 Sodium hydroxide + 5.4 0.24Succinic acid 4.7 0.66 4.1 2.18 Sodium hydroxide + 5.4 0.15 Glutamicacid 4.7 0.49 4.1 2.27

As can be seen in Table 4, it was confirmed that in the case ofincluding malic acid, Substance A related to sodium picosulfate(4-[(pyridine-2-yl)(4-hydroxyphenyl)methyl]phenyl sodium sulfate) isgenerated at 2.0 wt. % or less in the above-mentioned pH range.

Hereinafter, embodiments of the present invention will be described withreference to the accompanying drawings.

FIG. 1 is a process flow diagram illustrating a method of preparing apharmaceutical liquid composition according to an embodiment of thepresent invention.

The method of preparing a pharmaceutical liquid composition may includethe steps of weighing citric acid and magnesium oxide to prepare amixture (S110), mixing malic acid and sodium hydroxide with the mixtureprepared in step S110 (S120), mixing sodium picosulfate with the mixtureprepared in step S120 (S130), and adding purified water to the mixturein step S130 (S140).

In step S110, a pH adjuster, a stabilizer, a sweetener and the like maybe added to the mixture.

In some cases, step S110 and step S120 may be performed at the sametime, and steps S110, S120 and S130 may be performed at the same time.Further, although steps S110, S120 and S130 have been illustrated in theorder mentioned, the order is not limited thereto.

Although the embodiments of the present invention have been disclosedfor illustrative purposes, those skilled in the art will appreciate thatvarious modifications, additions and substitutions are possible, withoutdeparting from the scope and spirit of the invention as disclosed in theaccompanying claims.

The invention claimed is:
 1. A method of treatment for cleaning thecolon of a subject in need thereof, comprising orally administering tothe subject an effective amount of a pharmaceutical compositioncomprising sodium picosulfate, magnesium oxide, citric acid, and malicacid, wherein the pharmaceutical composition is a solution with a pH inthe range from 4.1 to 5.4.
 2. The method of claim 1, wherein in themethod is for pretreatment for colonoscopy.
 3. The method of claim 1,wherein in the method is for pretreatment for surgery.
 4. The method ofclaim 1, wherein in the method is for pretreatment for surgery colonX-ray.
 5. The method of claim 1, wherein the sodium picosulfate, themagnesium oxide, the citric acid, and the malic acid are present in aweight ratio of 0.003 to 0.009:1 to 3:3.5 to 10.5:0.01 to 13 (sodiumpicosulfate:magnesium oxide:citric acid:malic acid).
 6. The method ofclaim 1, wherein the composition further comprises one or moreexcipients chosen from pH adjusters, stabilizers, preservatives,sweeteners, and fragrance ingredients.
 7. The method of claim 1, whereinthe composition further comprises acesulfame potassium.
 8. The method ofclaim 1, wherein the composition further comprises disodium edetate. 9.The method of claim 1, wherein the composition further comprises sodiumbenzoate.
 10. The method of claim 1, wherein the composition furthercomprises sodium hydroxide.
 11. The method of claim 1, wherein thecomposition further comprises sucralose.
 12. A method of treatment forcleaning the colon of a subject in need thereof, comprising orallyadministering to the subject an effective amount of a pharmaceuticalcomposition comprising sodium picosulfate, magnesium oxide, citric acid,and malic acid, wherein the pharmaceutical composition is a liquid witha pH ranging from 4.1 to 5.4, and further wherein the sodiumpicosulfate, the magnesium oxide, the citric acid, and the malic acidare present in a weight ratio of about 0.005:1.75:6:4.19 (sodiumpicosulfate:magnesium oxide:citric acid:malic acid).
 13. The method ofclaim 12, wherein in the method is for pretreatment for colonoscopy. 14.The method of claim 12, wherein in the method is for pretreatment forsurgery.
 15. The method of claim 12, wherein in the method is forpretreatment for surgery colon X-ray.
 16. The method of claim 12,wherein the composition further comprises one or more excipients chosenfrom pH adjusters, stabilizers, preservatives, sweeteners, and fragranceingredients.
 17. The method of claim 12, wherein the composition furthercomprises acesulfame potassium.
 18. The method of claim 12, wherein thecomposition further comprises disodium edetate.
 19. The method of claim12, wherein the composition further comprises sodium benzoate.
 20. Themethod of claim 12, wherein the composition further comprises sodiumhydroxide.
 21. The method of claim 12, wherein the composition furthercomprises sucralose.